Suzuki et al.
1H NMR (400 MHz, CDCl3) δ ) 1.50 (bd, 1H), 1.78 (s, 3H),
2.97 (dd, 1H, J ) 8.8, 14.0 Hz), 3.24 (dd, 1H, J ) 5.7, 14.0
Hz), 4.86 (m, 1H), 5.05 (m, 2H), 5.55 (bd, 1H), 7.18-7.39 (m,
10H); 13C NMR (100 MHz, CDCl3) δ ) 9.9, 36.9, 56.1, 68.7,
127.6, 128.6, 128.8, 129.0, 129.1, 129.3, 129.6, 129.7, 136.3,
202.5; IR (neat) 1032, 1194, 1250, 1522, 1694 cm-1; MS (+FAB)
m/z 360 (MH+); HRMS (+FAB) calcd for C19H22NO4S (MH+)
360.1270, found 360.1269.
(3S)-1-Acetoxy-3-(N,N-Dibenzyl)amino-1-methylthio-2-
oxo-4-phenylbutane (4b).
To a solution of crude 3b (173.0 mg, prepared above) in a
mixture of dichloromethane (4 mL) and pyridine (0.1 mL) was
added dropwise acetyl chloride (0.05 mL, 0.703 mmol) with
cooling in an ice bath, and the resulting mixture was stirred
for 30 min at ambient temperature. HCl (0.5 M, 5 mL) and
dichloromethane (10 mL) were added to the mixture and
extracted. The organic layer was separated and washed with
saturated NaHCO3 aqueous solution (5 mL) and saturated
NaCl aqueous solution (8 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The resulting
residue was purified through preparative silica gel thin-layer
chromatography to obtain 4b (144.8 mg, 0.324 mmol, 91.1%
from 2b in two steps) as colorless crystals. The diastereomeric
(3S)-1-Acetoxy-3-(N-benzyloxycarbonyl)amino-1-meth-
ylthio-2-oxo-4-phenylbutane (4a).
To a solution of 3a (404.5 mg, 1.125 mmol) in a mixture of
dichloromethane (11 mL) and pyridine (0.27 mL) was added
dropwise acetyl chloride (0.12 mL, 1.69 mmol) with cooling in
an ice bath, and the resulting mixture was stirred for 3 h at
ambient temperature. HCl (0.5 M, 20 mL) and dichlo-
romethane (15 mL) were added to the mixture and extracted.
The organic layer was separated and washed with saturated
NaHCO3 aqueous solution (12 mL) and saturated NaCl aque-
ous solution (15 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The resulting residue
was purified through silica gel column chromatography (n-
hexane/ethyl acetate ) 5/1 to 4/1) to obtain 4a (413.3 mg, 1.029
mmol, 91.5% from 3a) as colorless crystals. The diastereomeric
1
ratio was about 20:1 by the integral ratio in H NMR.
1H NMR (400 MHz, CDCl3) δ ) 1.22 (s, 3H), 2.11 (s, 3H),
3.25 (dd, 1H, J ) 12.2, 12.2 Hz), 3.70-3.80 (m, 1H), 4.21 (bd,
2H), 4.44 (bd, 2H), 4.85 (bd, 1H), 6.53 (bd, 1H), 6.94-7.85 (m,
15H); 13C NMR (100 MHz, CDCl3) δ ) 10.6, 20.8, 56.3, 62.6,
63.3, 68.8, 77.6, 127.7, 128.9, 129.5, 129.8, 130.0, 130.8, 131.5,
170.5, 194.7; IR (neat) 967, 1081, 1212, 1372, 1428, 1725 cm-1
;
MS (+FAB) m/z 448 (MH+); HRMS (+FAB) calcd for C27H30-
NO3S (MH+) 448.1946, found 448.1938.
1
ratio was about 1:1 by the integral ratio in H NMR.
(3S)-1-Acetoxy-3-(N,N-Dibenzyl)amino-1-methylthio-2-
oxo-4-phenylbutane (4b). One-Pot Reaction from 2b.
2b (102.4 mg, 0.252 mmol) was dissolved in a mixture of
dichloromethane (2 mL), pyridine (0.2 mL), and acetic anhy-
dride (0.2 mL); then 4-dimethylamino pyridine (3 mg) was
added to the solution. The resulting mixture was stirred for
10 days at ambient temperature. HCl (1 M, 10 mL) and ethyl
acetate (10 mL) was added to the mixture and extracted. The
organic layer was separated and washed with water (6 mL),
saturated NaHCO3 aqueous solution (7 mL), and saturated
NaCl aqueous solution (7 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The resulting
residue was purified through preparative silica gel thin-layer
chromatography to obtain 4b (86.6 mg, 0.193 mmol, 76.8%
from 2b) as a colorless solid.
1H NMR (400 MHz, CDCl3) (mixture of about 1:1 of dia-
stereomeric isomers) δ ) 1.75 (s, 3/2H), 1.98 (s, 3/2H), 2.14 (s,
3/2H), 2.17 (s, 3/2H), 2.99 (m, 1H), 3.17 (m, 1H), 4.97-5.29
(m, 4H), 6.01 (s, 1/2H), 6.15 (s, 1/2H), 7.17-7.37 (m, 10H); 13
C
NMR (100 MHz, CDCl3) δ ) 10.8, 20.6, 36.5, 56.0, 67.3, 126.9,
127.3, 128.1, 128.2, 128.5, 128.7, 129.4, 129.5, 136.1, 169.8,
196.4; IR (neat) 1044, 1108, 1212, 1264, 1524, 1692, 1750 cm-1
;
MS (+FAB) m/z 402 (MH+); HRMS (+FAB) calcd for C21H24-
NO5S (MH+) 402.1375, found 402.1365.
(3S)-1-Acetoxy-3-(N-benzyloxycarbonyl)amino-1-meth-
ylthio-2-oxo-4-phenylbutane (4a), One-Pot Reaction from
2a.
2a (166.2 mg, 0.462 mmol) was dissolved in a mixture of
dichloromethane (4.6 mL), pyridine (0.5 mL), and acetic
anhydride (0.5 mL); then 4-dimethylamino pyridine (3 mg) was
added to the solution. The resulting mixture was stirred for
17.5 h at ambient temperature. HCl (1 M, 10 mL) and ethyl
acetate (15 mL) were added to the mixture and extracted. The
organic layer was separated and washed with saturated
NaHCO3 aqueous solution (10 mL) and saturated NaCl aque-
ous solution (10 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The resulting residue
was purified through preparative silica gel thin-layer chro-
matography to obtain 4a (124.5 mg, 0.310 mmol, 67.1% from
2a) as a colorless solid.
Methylthio (2S,3S)- and (2R,3S)-2-acetoxy-3-(N-benz-
yloxycarbonyl)amino-4-phenylbutylate (5a).
To a solution of 4a (124.5 mg, 0.310 mmol) in toluene (3
mL) was added 1,8-diazabicyclo [5.4.0] uncec-7-ene (0.05 mL,
0.334 mmol), and the mixture was stirred for 1 h 55 min at
ambient temperature. HCl (1 M, 7 mL) and ethyl acetate (15
mL) was added to the mixture and extracted. The organic layer
was separated and washed with saturated NaHCO3 aqueous
solution (7 mL) and saturated NaCl aqueous solution (7 mL),
and then dried over anhydrous Na2SO4, and concentrated
under reduced pressure. The resulting residue was purified
through preparative silica gel thin-layer chromatography to
obtain 5a (121.4 mg, 0.302 mmol, 97.5% from 4a) as a colorless
solid. The diastereomeric ratio was about 6:4 by the integral
(3S)-3-(N,N-Dibenzyl)amino-1-hydroxy-1-mehtylthio-
2-oxo-4-phenylbutane (3b).
To a solution of 2b (309.6 mg, 0.763 mmol) in dimethyl
sulfoxide (6 mL) was added 2 M HCl (1.5 mL). After the
mixture was stirred for 16 h at ambient temperature, it was
cooled in an ice bath and neutralized with saturated NaHCO3
aqueous solution (5 mL). Water (10 mL) and ethyl acetate (20
mL) was added to the mixture and extracted. After the organic
layer was separated, the resulting aqueous layer was extracted
twice with ethyl acetate (10 mL). The combined organic layers
were washed with water (20 mL) and saturated NaCl aqueous
solution (20 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The resulting residue was
crystallized in n-hexane/ethyl acetate to give crude 3b (371.5
mg) as a slightly yellowish solid.
1H NMR (400 MHz, CDCl3) δ ) 1.71 (s, 3H), 3.04 (dd, 1H,
J ) 11.3, 12.8 Hz), 3.24-3.30 (m, 1H), 3.83-3.94 (m, 1H), 4.04
(bd, 1H), 4.31 (br, 1H), 4.65 (m, 2H), 4.77 (s, 1H), 5.03 (dd,
1H, J ) 3.4, 11.3 Hz), 6.90-7.82 (m, 15H); 13C NMR (100 MHz,
CDCl3) δ ) 13.3, 49.2, 56.4, 61.0, 80.6, 129.4, 129.5, 129.6,
129.7, 129.7, 129.8, 129.8, 130.5, 201.5; IR (neat) 974, 1125,
1428, 1569, 1713 cm-1; MS (+FAB) m/z 406 (MH+); HRMS
(+FAB) calcd for C25H28NO2S (MH+) 406.1841, found 406.1865.
1
ratio in H NMR. For determination of the absolute configu-
ration, the analyses of 6c that had been obtained by the
following experiments conformed to the referential sample of
(S,S)-6c prepared by the known reaction via cyanation to
dibenzylamino aldehyde.7
1H NMR (400 MHz, CDCl3) (mixture of about 3:2 of dia-
stereomeric isomers) δ ) 2.18 (s, 3H), 2.25 (s, 6/5H), 2.31 (s,
9/5H), 2.77-2.99 (m, 2H), 4.53 (m, 1H), 4.81 (bd, 2/5H, -NH),
5.04 (d, 2H, J ) 2.6 Hz), 5.11 (bd, 3/5H, -NH), 5.21 (d, 3/5H,,
J ) 2.4 Hz), 5.43 (d, 2/5H, J ) 4.0 Hz), 7.16-7.38 (m, 10H);
13C NMR (100 MHz, CDCl3) δ ) 11.6, 21.0, 38.9, 54.1, 67.3,
78.1, 127.4, 128.5, 128.9, 129.0, 129.2, 129.6, 136.8, 155.9,
170.1, 197.9; IR (neat) 1042, 1214, 1524, 1690, 1754 cm-1; MS
(+FAB) m/z 402 (MH+); HRMS (+FAB) calcd for C21H24NO5S
(MH+) 402.1375, found 402.1388.
Methylthio (2S,3S)- and (2R,3S)-2-Acetoxy-3-(N,N-
dibenzyl)amino-4-phenylbutylate (5b).
To a solution of 4b (50.6 mg, 0.113 mmol) in dimethyl
formamide (1.1 mL) cooled to -30 °C was added 1,8-
diazabicyclo[5.4.0]uncec-7-ene (0.02 mL, 0.134 mmol), and the
7322 J. Org. Chem., Vol. 70, No. 18, 2005